Search

Aims Distinctive types of polymorphic ventricular tachycardia (VT) respond differently to different forms of therapy. We therefore performed the present study to define the electrocardiographic characteristics of different forms of polymorphic VT. Methods and results We studied 190 patients for whom the onset of 305 polymorphic VT events was available. The study group included 87 patients with coronary artery disease who had spontaneous polymorphic VT triggered by short-coupled extrasystoles in the absence of myocardial ischaemia. This group included 32 patients who had a long QT interval but nevertheless had their polymorphic VT triggered by ectopic beats with short coupling interval, a subcategory termed ‘pseudo-torsade de pointes] (TdP). For comparison, we included 50 patients who had ventricular fibrillation (VF) during acute myocardial infarction (‘ischaemic VF’ group) and 53 patients with drug-induced TdP (‘true TdP’ group). The QT of patients with pseudo-TdP was (by definition) longer than that of patients with polymorphic VT and normal QT (QTc 491.4 ± 25.2 ms vs. 447.3 ± 55.6 ms, P Conclusions The coupling interval helps discriminate between polymorphic VT that occurs despite a long QT interval (pseudo-TdP) and polymorphic arrhythmias striking because of a long QT (true TdP).

Introduction Ca2+/calmodulin-dependant protein kinase II (CaMKII) activity in cardiomyocytes plays a crucial role in their contractility. Increased CaMKII signalling has been associated with mechanical stretch, often caused in the border zone of myocardial infarction. CaMKII upregulation causes a mishandling of intracellular calcium, a precursor of multiple pro-arrhythmic mechanisms, such as early afterdepolarisations. Purpose In this study, we aim to quantify the effects of KN-93 -a CaMKII inhibitor- on wave dynamics, in order to investigate its effectiveness as an anti-arrhythmic agent. Methods An isolated Langendorff model was constructed based on rabbit hearts (n=18) and posteriorly induced to fibrillation. An epicardial multielectrode array (121 electrodes) was used for recording the electrical activity. Mechanical stretch was induced by pushing the anterior myocardial wall from the left-ventricular cavity. Then, a frequency analysis was conducted for the following conditions: before drug infusion, during infusion, during infusion plus stretch, and during infusion post-stretch. Nine hearts represented the untreated group, and the other nine were infused with KN-93 at a concentration of 10 nM (less than 3% of the IC50 value). Results Prior to stretch induction, KN-93 caused no effects in the spectral concentration (SC) and average dominant frequency (ADF) calculated on the infused rabbit hearts. Nevertheless, intrasubject measurements revealed statistically significant differences (p Conclusion CaMKII inhibitors show cardioprotective potential, even at very low concentrations. Further research is required to investigate the therapeutic use of these compounds in conditions of intracellular calcium mishandling and its concomitant life-threatening consequences, such as heart failure or Torsade de Pointes. KN-93 reduces stretch-induced changes Funding Acknowledgement Type of funding source: Public Institution(s). Main funding source(s): Universitat de València; Generalitat Valenciana - Prometeo; Carlos III, CIBERCV

Background Experimental data have shown that some anticancer drugs can affect cardiac repolarization and induce life-threatening cardiac arrhythmias. Objective To identify anti-cancer drugs associated with the occurrence of sudden death (SD) and ventricular arrhythmias using the World Health Organization individual case safety report (ICSR) database, Vigibase. Methods The system organ class MEDRA was used to identify cases as ICSR with the terms sudden death, sudden cardiac death, cardiac arrest, ventricular fibrillation, ventricular tachycardia, ventricular arrhythmia and torsades de pointes (named as SD events) from Nov 1967 to Nov 2019. We used the ATC code L01 which regroups 219 antineoplastic agents. A disproportionality analysis was performed to estimate of relative Odds Ratio (ROR). Signals were considered significant when the lower boundary of the 99.97% confidence interval (ROR0.25) was ≥1. Results Among the 2,170,203 adverse events associated with anticancer drugs, 11,979 (0.55%) concerned SD events. A total of 49 molecules were significantly associated with SD events, among which 4 were withdrawn from market. These molecules were mainly anti-metabolites (20.0%), chemicals such as arsenic (17.8%,), anthracyclins (8.9%) and alkaloids (8.9%). When agents were grouped according to their mode of actions, the highest risks were observed for platinum-based drugs (n=1628 cases, ROR0.25=1.2) and anthracyclins (n=1323 cases, ROR0.25=1.3). While the risk for SD or severe arrhythmias was reported in the drug label for 29 agents (64.4%), we found that this risk was not identified or mentioned for 16 agents (35.5%). Conclusions We identified 49 anticancer drugs that are significantly associated with SD events overreporting. Appropriate monitoring and preventive measures should be considered for patients receiving these drugs. Funding Acknowledgement Type of funding source: None

Introduction It is well recognized that early identification of drug-induced proarrhythmic safety risks is crucial to drug development for ethical, animal sparing and costs reduction considerations. The availability, however, of easily accessible, user-friendly tools for real time assessments of the proarrhythmic potential of chemical compounds has been lacking. The novel Tx index, implemented in the presented web-based tool, was applied to a dataset of 84 compounds. Materials and methods The tool is based on 206,766 cellular simulations of compound-induced effects on Action Potential Duration (APD) in isolated endocardial, midmyocardial, and epicardial cells and on 7,072 tissue simulations on QT prolongation in a virtual tissue. Simulations were performed by blocking the slow and the fast components of the delayed rectifier current (IKs and IKr, respectively) and the L-type calcium current (ICaL) at different levels. Based on these simulations, four Tx indices were defined as the ratio of drug concentration leading to a 10% prolongation of the APDendo, APDmid, APDepi or QT over the maximum Effective Free Therapeutic Plasma Concentration (EFTPC), respectively. A dataset of 44 non-torsadogenic and 40 torsadogenic drug compounds was used to validate the performance of the tool. The workflow of the web-based tool was built on the cloud environment, in compliance with the highest standards of security and privacy. hERG test (positive response: hERG pIC50 >6) was applied to the 84 compounds to compare performances. Results Receiver operating characteristic (ROC) curves were constructed on the four estimated Tx indices for each compound in the dataset to enable the identification of torsadogenic potential cut-off values2. These were identified as 8, 8, and 6.4 for Tx-APDendo, Tx-APDmid, Tx-APDepi and as 9.2 for Tx-QT, respectively. The classification of the 84 compounds resulted in an accuracy ranging between 87% and 88% for the four Tx indices Tx-APDendo, Tx-APDmid, Tx-APDepi and Tx-QT. Discussion and conclusion hERG block exhibits poor performance. When applying the hERG test to the 84 compounds, it exhibited a TPR of 55%, a TNR of 89%, and an A of 73%, in close agreement with previous studies. In comparison, the in silico Tx tests described in this study yield TPRs of 85%, TNRs of 86–89% and As of 86–87%. This method does not include drug effects on Na+ channels, which is related to the misclassification of 3 compounds (quetiapine, ranolazine, and lamotrigine – significant Na+ channels blockers at EFTPC). Future work will include this channel. The presented web-based tool is a highly innovative method for an accurate torsadogenic risk assessment. Each assessment required only a few seconds of computational time. Illustration workflow of the web tool Funding Acknowledgement Type of funding source: None

Background Left cardiac sympathetic denervation (LCSD) is an effective anti-fibrillatory, minimally invasive therapy for patients with either LQTS or CPVT. As a pre-ganglionic fiber resection, re-growth or re-innervation is not possible. However, if a suboptimal CSD was performed, chances for post-LCSD breakthrough cardiac events (BCEs) are increased. Purpose To examine the prevalence and outcomes of patients requiring a re-do LCSD. Methods We performed a retrospective review of the 251 LQTS and CPVT patients who underwent CSD (mostly LCSD) at our institution to identify the subset referred for additional CSD because of recurrent BCEs after their primary LCSD that was performed elsewhere. Clinical data on symptomatic status prior to diagnosis and BCEs after first surgery as well as the surgical reports were reviewed to determine the reasons for the repeat procedure. Results Among the 15 patients (6% overall, 6 female; 13 LQTS, 2 CPVT) referred for additional CSD, 3 patients (20%) had a re-do LCSD performed instead of a sequential RCSD because of incomplete resection with the primary LCSD. Patient 1 is a male with Jervell-and-Lange Nielsen Syndrome (JLNS; KCNQ1-K421fs9X; KCNQ1-N365H), who first experienced syncope with torsades at age 3 after which a primary bilateral CSD was performed elsewhere. He had 2 BCEs and at age 12 underwent re-do LCSD, where his left-sided T2-T4 sympathetic chain with remnants of T1 were found to be intact. Patient 2 is a male who had 3 cardiac events prior to diagnosis (genotype negative LQTS) and LCSD at age 3. Following 3 BCEs, he underwent re-do LCSD at age 5 where scarring of T3 and intact stellate ganglion were found. Patient 3 is an adult female with CPVT (RYR2-deletion exon 3) who had multiple syncopal events, out-of-hospital arrest (leading to ICD) and 2 ICD-storms before primary bilateral CSD. Re-do LCSD was performed after identifying an intact left stellate ganglion and T2. Conclusions Before performing a primary bilateral CSD, proceeding to a RCSD after post-LCSD BCEs, or doing a videoscopic LCSD in the first place, it must be recognized that LCSD's success hinges on fully resecting the lower half of the stellate ganglion and the sympathetic chain through T4. Anything less is a partial denervation and likely ineffective procedure. Funding Acknowledgement Type of funding source: None

Background Dexmedetomidine is increasingly employed for conscious sedation during electrophysiological procedures. Recent experimental data have suggested direct effects of dexmedetomidine on cardiac electrophysiology. The aim of the present study was to assess the effects of dexmedetomidin on drug-induced QT-prolongation. Methods and results In 12 isolated rabbit hearts the macrolide antibiotic erythromycin (300μM) was infused as a potent Ikr blocker after obtaining baseline data. Eight endo- and epicardial monophasic action potentials and a simultaneously recorded 12-lead ECG showed a significant prolongation of QT-interval (+25ms, p Lowering of potassium concentration in bradycardic AV-blocked hearts resulted in the occurrence of early afterdepolarizations (EAD) and drug induced proarrhythmia with torsade de pointes in 6 of 12 erythromycin-treated hearts (40 episodes). Additional infusion of dexmedetomidine reduced the occurrence of torsade de pointes (4 of 12 hearts, 9 episodes). Conclusion Infusion of dexmedetomidine resulted in a reduction of spatial dispersion of repolarization in the presence of a prolonged repolarization period. This resulted in a reduction of torsade de pointes with dexmedetomidine. Furthermore, an increase of ventricular refractory periods reduced inducibility of ventricular arrhythmias. Thus, in an experimental setting dexmedetomidine shows significant antiarrhythmic effects, which may influence electrophysiologic findings during clinical electrophysiologic studies. This needs to be studied in the clinical setting. Funding Acknowledgement Type of funding source: None

Background The anesthetized, chronic complete atrioventricular block (CAVB) dog model allows reproducible inducibility of Torsade de Pointes (TdP) arrhythmias due to ventricular remodeling and after a challenge with an IKr-blocker. High rate pacing (HRP) prevents ventricular arrhythmias, but has long-term detrimental effects on cardiac function when applied continuously. Temporal dispersion of repolarization, quantified as short-term variability (STV), increases prior to ventricular arrhythmias and has been proposed as a marker to guide HRP. Purpose A proof-of-principle study to show STV determined automatically and in real-time by an ICD can guide HRP to prevent imminent ventricular arrhythmias. Methods Eight CAVB dogs were implanted with an ICD (Medtronic, lead in the right ventricular (RV) apex), with software to automatically determine STV online (STV-ICD). STV was determined from the activation recovery interval (ARI) of 31 consecutive beats with the formula: STV = Σ|ARI(n+1) − ARI(n)|/(N*√2). The CAVB dogs were challenged twice with dofetilide (0.025 mg/kg i.v. in 5 minutes or until the first TdP). In the first experiment, the individual STV-ICD threshold was determined prior to the first arrhythmic event and programmed into the ICD. In a serial experiment, HRP was initiated automatically once the STV-ICD threshold was reached, by gradually increasing the heart rate to 100 bpm. Occurrence of TdPs was monitored for 10 minutes from the start of dofetilide infusion in both experiments. During HRP, STV was measured offline from RV electrograms (EGM) and left ventricular (LV) monophasic action potential durations (MAPD) (STV-offline). Results During the inducibility experiment, 8/8 dogs had repetitive TdPs and STV-ICD increased from 0.96±0.42 to 2.10±1.26 ms* (*p Conclusion Temporal dispersion of repolarization, quantified as STV, can guide HRP automatically by an ICD to prevent ventricular arrhythmias. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Dutch Heart Foundation Public Private Partnership

Background The diagnosis of concealed cardiomyopathies in patients with ventricular arrhythmias (VAs) is one of the major challenging issues faced by physicians. Purpose We aimed at reporting the cardiomyopathic substrate in patients with recurrent arrhythmias of ventricular origin. Methods Consecutive patients with unexplained VAs underwent a complete diagnostic work-out, including endomyocardial biopsy (EMB). Results Ninety-seven patients were enrolled (76.3% male, age 39.7±13.3 yrs). The presenting arrhythmic manifestation was aborted cardiac arrest in 30 (30.9%) patients, sustained ventricular tachycardia (VT) in 9 (9.3%), nonsustained VT in 15 (15.5%) and frequent premature ventricular complexes in 43 (44.3%). Overall, 350 biopsies were collected (3.6/patient). The incidence of procedure-related complications was 5.1% (n=5): 4 major complications (1 rupture of a tricuspid chorda tendinea w/o hemodynamic impairment, 1 dissection of right external iliac artery treated with stent, 1 thrombotic occlusion of left superficial femoral artery which required surgical treatment, 1 TIA) and 1 minor complication (groin hematoma) occurred. The final diagnosis was arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) (n=41; 42.3%), followed by myocarditis (n=20; 20.6%), dilated cardiomyopathy (n=6; 6.2%), cardiac sarcoidosis (n=6; 6.2%), and myocarditis in ARVD/C (n=5; 5.1%). Among the 25 patients whose final diagnosis was consistent with myocarditis, an acute stage of the disease was documented in 7 (7.2%), while a chronic myocarditis in 18 (18.5%). Additionally, according to medical history and diagnostic workout, in 2 of the 6 patients the dilated cardiomyopathy had a likely post-inflammatory etiology. Absence of myocardial abnormalities was documented in 15 (15.5%) patients: this group included 1 case of methadone-induced torsade de pointes. The remaining 4 (4.1%) patients were diagnosed with a cardiac hypertrophy (n=2, 2.1%, secondary to exercise or Fabry disease), a dilated mitochondrial cardiomyopathy (n=1, 1.0%), a dilated cardiomyopathy in Emery-Dreifuss muscular dystrophy (n=1; 1.0%). Conclusion In our series, approximately 45% of patients with unexplained VAs had a final diagnosis of ARVD/C.

Background Vernakalant is an antiarrhythmic agent designed for pharmacological conversion of recent onset of atrial fibrillation (AF) with combined action on cardiac potassium and sodium currents mainly concentrated in the atria. Purpose SPECTRUM was a post-authorisation safety study of vernakalant, conducted to collect information about real-life conditions of use and appropriate dosing, and to quantify possible medically significant risks associated with the use of vernakalant in real-world clinical practice. Methods This prospective and retrospective registry was conducted from Sep 2011 to Apr 2018 in 53 hospitals in EU countries including Austria, Denmark, Finland, Germany, Spain and Sweden. A total of 1,778 patients with 2,009 episodes of recent-onset AF received vernakalant and were followed up for 24 hours after the last infusion or until hospital discharge/end of medical encounter to obtain information on medically significant health outcomes of interest (HOIs, defined as significant hypotension, significant ventricular arrhythmia, significant atrial flutter, significant bradycardia), and serious adverse events (SAEs). Results In more than 99% of treatments, vernakalant was used in accordance to the labelled indication for conversion of AF for non-surgery (94.7%) or post-cardiac surgery patients (5.2%). Vernakalant was administered in the emergency department in 64.2% of cases, with a median stay of 7.5 hours and successfully converted 70.2% (95% CI: 68.1–72.2) of patients in the effectiveness analysis population with a median time to conversion of 11 minutes (95% CI: 8.0–27.0). A total of 19 HOIs were reported in 17 patients (0.8%, 95% CI: 0.5– .4%) with individual HOIs ranging from Conclusion(s) SPECTRUM is, to our knowledge, the largest drug registry conducted on the cardioversion of recent onset AF. The cumulative data from 2,009 vernakalant treatment episodes demonstrate an incidence of HOIs and SAEs similar or lower to what has been reported in earlier vernakalant IV clinical trials. The observed conversion rate was higher than reported in pivotal trials supporting vernakalant's efficacy and allowing early discharge. Acknowledgement/Funding Study funded by Correvio International Sarl, Geneva, Switzerland

Aim Prolonged and dispersed left-ventricular (LV) contraction is present in patients with long-QT syndrome (LQTS). Electrical and mechanical abnormalities appear most pronounced in symptomatic individuals. We focus on the 'electromechanical window' (EMW; duration of LV-mechanical systole minus QT interval) in patients with genotyped LQTS. Profound EMW negativity heralds torsades de pointes in animal models of drug-induced LQTS. Methods and results We included 244 LQTS patients from three centres, of whom 97 had experienced arrhythmic events. Seventy-six matched healthy individuals served as controls. QT interval was subtracted from the duration of Q-onset to aortic-valve closure (QAoC) midline assessed non-invasively by continuous-wave echocardiography, measured in the same beat. Electromechanical window was positive in controls but negative in LQTS patients (22 +/- 19 vs. -43 +/- 46 ms; P

Drug-induced Torsades de Pointes is a rare, unpredictable, and life-threatening serious adverse event. It can be caused by both cardiac and non-cardiac drugs and has become a major issue in novel drug development and for the regulatory authorities. This review describes the problem, predisposing factors, and the underlying genetic predisposition as it is understood currently. The future potential for pharmacogenomic-guided and personalized prescription to prevent drug-induced Torsades de Pointes is discussed. Database searches utilized reports from www.qtdrugs.org up to January 2012, case reports and articles from www.pubmed.com up to January 2012, and the British National Formulary edition at www.bnf.org.

AIMS: Torsades de pointes arrhythmias (TdP) occur by definition in the setting of prolonged QT intervals. Animal models of drug induced Long-QT syndrome (dLQTS) have shown higher predictive value for proarrhythmia with beat-to-beat variability of repolarization duration (BVR) when compared with QT intervals. Here, we evaluate variability of QT intervals in patients with a history of drug-induced long QT syndrome (dLQTS) and TdP in absence of a mutation in any of the major LQTS genes. METHODS AND RESULTS: Twenty patients with documented TdP under drugs with QT-prolonging potential were compared with 20 matched control individuals. An observer blinded to diagnosis manually measured lead-II, RR, and QT intervals from 30 consecutive beats. BVR was determined from Poincare plots of QT intervals as short-term variability (STV(QT) = Sigma|QT(n)(+1) - QT(n)|/[30 x radical2]). QRS interval and cycle length was comparable between study groups and controls. No difference was found in QTc between dLQTS and controls (428 +/- 25 vs. 421 +/- 34 ms, P = 0.26), whereas STV(QT) was significantly higher in dLQTS when compared with controls (8.1 +/- 3.7 vs. 3.6 +/- 1.3 ms, P = 0.001). Proarrhythmic predictive power of STV(QT) was superior to that of the QTc interval (AUC: 0.89 vs. 0.57, 95% CI: 0.79-0.99 vs. 0.39-0.75). CONCLUSION: In the absence of QTc prolongation, baseline STV(QT) characterized patients with documented drug-induced proarrhythmia. STV(QT) could prove to be a useful non-invasive, easily obtainable parameter aiding the identification of the patient at risk for potentially life threatening arrhythmia in the context of drugs with QT prolonging potential.

Aims To assess the association between the use of non-cardiac QTc-prolonging drugs and the risk of sudden cardiac death.Methods and results A population-based case-control study was performed in the Integrated Primary Care Information (IPCI) project, a longitudinal observational database with complete medical records from more than 500 000 persons. All deaths between 1 January 1995 and 1 September 2003 were reviewed. Sudden cardiac death was classified based on the time between onset of cardiovascular symptoms and death. For each case, up to 10 random controls were matched for age, gender, date of sudden death, and general practice. The exposure of interest was the use of non-cardiac QTc-prolonging drugs. Exposure at the index date was categorized into three mutually exclusive groups of current use, past use, and non-use. The study population comprised 775 cases of sudden cardiac death and 6297 matched controls. Current use of any non-cardiac QTc-prolonging drug was associated with a significantly increased risk of sudden cardiac death (adjusted OR: 2.7; 95% CI: 1.6-4.7). The risk of death was highest in women and in recent starters.Conclusion The use of non-cardiac QTc-prolonging drugs in a general population is associated with an increased risk of sudden cardiac death.

Aims Drug-induced QTc-prolongation, resulting from inhibition of HERG potassium channels may lead to serious ventricular arrhythmias and sudden death. We studied the quantitative anti-HERG activity of pro-arrhythmic drugs as a risk factor for this outcome in day-to-day practice. Methods and results All 284 426 case reports of suspected adverse drug reactions of drugs with known anti-HERG activity received by the International Drug Monitoring Program of the World Health Organization (WHO-UMC) up to the first quarter of 2003, were used to calculate reporting odds ratios (RORs). Cases were defined as reports of cardiac arrest, sudden death, torsade de pointes, ventricular fibrillation, and ventricular tachycardia (n ¼ 5591), and compared with non-cases regarding the anti-HERG activity, defined as the effective therapeutic plasma concentration (ETCPunbound) divided by the HERG IC50 value, of suspected drugs. We identified a significant association of 1.93 (95% CI: 1.89–1.98) between the anti-HERG activity of drugs, measured as log10 (ETCPunbound/IC50), and reporting of serious ventricular arrhythmias and sudden death to the WHO-UMC database. Conclusion Anti-HERG activity is associated with the risk of reports of serious ventricular arrhythmias and sudden death in the WHO-UMC database. These findings are in support of the value of pre-clinical HERG testing to predict pro-arrhythmic effects of medicines.

Aims Women have a longer QT interval and a greater incidence of torsades de pointes than men. It has been suggested that oestrogens may influence the duration of cardiac repolarization. We thus investigated the influence of oestradiol (E2) on ventricular repolarization within the physiological concentration range of this hormone. Methods and results We studied QT interval duration in 21 healthy women aged 18 to 35 years with regular menstrual cycle (mean duration: 29±1 days) during two periods associated with a wide range of oestradiol plasma levels: low level during menses (105±34pmol/l) and high level during the pre-ovulatory phase (750±277pmol/l). We used heart rate-independent assessment of QT. QT–RR pairs were measured over a wide range of RR intervals obtained at rest and during a sub-maximal exercise test. Using a monoexponential nonlinear curve fitting for the QT–RR relation, the QT1000msduring nadir and peak oestradiol periods was then determined for each subject. QT1000msinterval was not different between both study periods: 382.1±18.4ms at peak versus 382.2±19.4ms at nadir oestradiol level ( P =0.98). Conclusion No significant change in QT interval duration was observed within the large range of physiological E2 variations found during the menstrual cycle.

The members of the Task Force on Sudden Death dedicate this paper to the memory of our former friend and colleague, Professor Ronald W. F. Campbell. Ronnie spent his life working in the field of sudden cardiac death; he contributed much and helped many. But his own life fell victim to this very problem, sadly illustrating its unexpected nature. With Ronnie’s memory in mind the Task Force has worked diligently to describe the extent of our expanding knowledge in this field, hoping that our small contribution might help to appease his sad and sudden death.

To minimize drug problems in the treatment of supraventricular tachycardias, it is important to understand the spectrum of adverse events and to identify patients at high risk for these problems. Adverse cardiac and non-cardiac effects are associated, to varying degrees, with currently available antiarrhythmics. Cardiac adverse events include the development of rhythm disturbances or exacerbation of heart failure. Serious rhythm disturbances, such as ventricular tachycardia or torsades des pointes, may result in syncope or death. In a meta-analysis of six randomized trials of quinidine vs placebo for atrial fibrillation, 1.8% of quinidine-treated patients died as opposed to 0.3% of placebo-treated patients. This increase in mortality was also noted in patients enrolled in the Stroke Prevention in Atrial Fibrillation Trial who were treated with type I antiarrhythmics. This increase in mortality was confined primarily to patients with a history of congestive heart failure. In a randomized trial of propafenone and sotalol for the treatment of atrial fibrillation, two out of 50 patients receiving sotalol died suddenly, one of whom had hypokalaemia-associated torsades des pointes. No patient receiving propafenone died during this trial. In a meta-analysis of propafenone's effect in treating supraventricular tachyarrhythmias in over 3100 adult patients, overall mortality was extremely low at 0.3%. Structural heart disease may increase the risk of antiarrhythmic agents. During impatient drug trials in patients treated for atrial fibrillation at Brigham and Women's Hospital, adverse cardiac events, primarily bradyarrhythmias, occurred in up to 15% of the patients. Older age and prior myocardial infarction were associated with an increased risk of adverse events. Adverse drug problems may be minimized by careful attention to electrolytes, medications, concomitant medical illnesses, and underlying conduction disease. Careful monitoring of patients during initiation of therapy, especially those patients with ischaemic heart disease, congestive heart failure, and who are older, may minimize drug-related problems.

This editorial refers to ‘Allele-specific RNA interference rescues the long-QT syndrome phenotype in human induced pluripotent stem cell cardiomyocytes’[†][1], by E. Matsa et al. , on page 1078 Congenital long-QT syndrome (LQTS) is a disorder of cardiac repolarization that manifests typically with ventricular arrhythmias such as torsades de pointes in patients with prolonged QT intervals in the ECG and structurally normal hearts. The known mutations affect genes encoding either subunits of cardiac ion channels or proteins involved in their regulation. Matsa and colleagues1 describe how they succeeded in using human induced pluripotent stem cell (hiPSC) technology not only to model a subtype of LQTS (LQT2), but also to evaluate a novel therapeutic approach using human cardiomyocytes derived from patient-specific hiPSCs. The authors generated cardiomyocytes from hiPSCs derived from a patient carrying a heterozygous mutation in the KCNH2 gene, corresponding to an A561T amino acid exchange in the KCNH2 -encoded protein hERG. Four hERG subunits co-assemble to form the pore of the ion channel generating the delayed rectifier potassium current IKr, an important determinant of the cardiac action potential duration. In accordance with the clinical phenotype of the patient, the hiPSC-derived cardiomyocytes displayed prolonged action potentials. The authors further demonstrated that, similar to other LQT2-causing ion channel mutations,2 the A561T mutation results in impaired ion channel trafficking: mutated subunits were not glycosylated properly and thus were retained in a perinuclear compartment instead of being integrated into the plasma membrane. Presumably due to co-assembly, the mutation also interfered with normal trafficking of the wild-type subunits in … [1]: #fn-2

Abnormal repolarization associated with torsades de pointes is expressed as QT prolongation. The physiological response to class Ia antiarrhythmic drugs is also reflected in prolongation of the QT interval. However, the essential difference between pathological and physiological prolongation is not clear. The purpose of this investigation was to differentiate between pathological and physiological changes in the repolarization waves of surface electrocardiograms (ECG) induced by class Ia drugs. In 18 patients without a history of torsades de pointes or syncope (control group), TU waves were compared before and after the administration of class Ia drugs (physiological response). In eight patients with torsades de pointes induced by class Ia drugs (torsades de pointes group), the TU waves at torsades de pointes were compared with those before drug administration (pathological response). In the control group, although the QTc (measured in lead II and corrected for heart rate by Bazett's formula) was increased significantly (0.40 +/- 0.04 to 0.44 +/- 0.05 s, P < 0.001), the U-amp (amplitude of the U wave measured in a precordial lead where the T and U waves were clearly differentiated) remained unchanged. In the torsades de pointes group, however, the QTc was increased (0.42 +/- 0.04 to 0.54 +/- 0.07 s, P < 0.02); the U-amp was also increased, significantly (0.09 +/- 0.07 to 0.27 +/- 0.18 mV, P < 0.05). Thus, enlargement of the U wave may help to differentiate between the physiological and pathological responses to class Ia drugs.

The role of increased dispersion of repolarization in the genesis of torsade de pointes and ventricular fibrillation has been well recognized generally, but not in the genesis of monomorphic ventricular tachycardia (VT). Monophasic action potentials (MAP) were therefore recorded simultaneously from the right ventricular (RV) apex (RVA) and outflow tract (RVOT) during sinus rhythm, RV pacing and programmed extra stimulation (PES) in 24 patients with VT. The activation time (AT), MAP duration at 90% repolarization (MAPd), and repolarization time (RT) were measured and their dispersions, defined as the differences in these parameters between RVA and RVOT, were calculated. During sinus rhythm and RV pacing, the dispersions of AT, MAPd and RT (dispersions) were significantly larger in the 17 patients with a VT induced than in those without. During PES, the dispersions were further augmented in the S2 beats in the seven patients with a sustained VT induced, the maximal dispersion of RT being 85 +/- 22 ms. Both the dispersion of AT and that of MAPd contributed to the dispersion of RT. In both of our two patients with a sustained VT induced during MAP recording, a marked increase in dispersions of RT (140 and 190 ms, respectively) was observed immediately before the initiation of the VT. A link between the dispersions and the inducibility of a monomorphic VT was found in our patients, which suggests that the increased dispersions play an important role in the genesis of a monomorphic VT.

Over the last decade, there has been an increasing confluence of experimental and clinical data on the gravity of proarrhythmic effects of class I agents. Over the same period, beta blockers have been shown to reduce mortality in a variety of subsets of patients. The properties of amiodarone and sotalol have also drawn attention to their potential as antifibrillatory compounds, perhaps acting principally by prolonging myocardial repolarization with little or no effect on conduction. However, amiodarone and sotalol are complex molecules and, therefore, attention is also focused on compounds that act simply by selective prolongation of cardiac repolarization. These agents have been termed 'pure' class III agents. The properties of sotalol, the prototype of class III agents, are of particular interest, as it is a racemic mixture of the levo- and dextro-isomers. The levo-isomer has 50 times the beta-blocking potency of the dextro-isomer, actions. Studies of the antiarrhythmic properties of beta blockers, d- and d,l-sotalol, and amiodarone may provide insights into the nature of class III actions. There is clinical evidence indicating that class III drugs exert a varying spectrum of antifibrillatory and proarrhythmic (characterized by torsade de pointes) actions for a given degree of prolongation of repolarization. These differences currently are not accountable in terms of specificity of their actions on ionic channels. There are differences between the so-called pure class III agents, such as sematilide, dofetilide and E-4031, and more complex compounds, such as sotalol and amiodarone, that also exert antiadrenergic actions. In the development of newer drugs an appropriate balance needs to be struck between proarrhythmic actions and the antifibrillatory properties. At present, it is unclear whether such antifibrillatory compounds should be relatively simple molecules with clearly-defined electrophysiologic profiles in terms of actions on ion channels, currents, receptors and pumps, or whether they need to be those with complex electropharmacologic profiles with multiplicity of actions.

Common clinical features in drug-induced torsade de pointes include hypokalemia and cycle-length prolongation just prior to initiation of the arrhythmia. In canine Purkinje fibres, drugs known to be associated with torsade de pointes, such as quinidine, sotalol or N-acetylprocainamide, consistently produce early after-depolarizations (EADs) and triggered activity at slow drive rates; for quinidine, these abnormalities are exaggerated by low extracellular potassium. Triggered activity can be abolished in vitro in two ways. First, action-potential shortening with abolition of EADs can be accomplished by increasing stimulation rates, beta-stimulation and action-potential shortening antiarrhythmics such as lidocaine. Second, triggered activity can be suppressed, with less prominent effects on EADs, by magnesium, alpha- and/or beta-adrenergic blockade and calcium-channel blockers. The parallels between these in vitro findings and clinical torsade de pointes suggest that EADs and triggered activity play a role in the genesis of the clinical arrhythmia. Further research directed at determining the mechanisms underlying the cellular abnormalities and their propagation to the whole heart should yield information that will increase the safety of antiarrhythmic therapy.

The coexistence of congenital complete heart block and QT prolongation represents a special type of arrhythmia. The electrophysiological and clinical characteristics of this syndrome were studied in eight patients suffering from congenital AV block and QT prolongation. Data from 22 patients suffering from congenital complete heart block only, served as a control. In the study group, the appearance of a torsade de pointes type of ventricular tachycardia could regularly be observed and the tachycardial attack could usually be provoked by ventricular extrastimuli. The corrected QT time was markedly prolonged; on ventricular stimulation, at higher pacing rates the QT interval shortened, but remained significantly higher than in the control group. Syncopal attacks--with the character of polymorphic tachycardia--appeared in each patient of the study group while occurring in only three patients from the control group. Patients were given pacemaker implants (using a higher pacing rate) and long-term administration of beta-receptor blockers. The outcome was favourable; no ventricular tachycardia or syncopal attack was observed in the follow-up period.

Torsade de pointes may occur as a complication of amiodarone therapy. We report a patient receiving amiodarone who was resuscitated from cardiovascular collapse and documented ventricular fibrillation. At subsequent electrophysiology study, while the patient was taking amiodarone therapy, monophasic action potentials with early after depolarisations were recorded which were not present when the patient was restudied 6 weeks after discontinuation of amiodarone. Early after-depolarisations may be important in the genesis of polymorphic ventricular tachycardia complicating amiodarone therapy.

Experimental data have suggested a relation between Torsades de Pointes and early post-depolarization (EPD). We have studied the effect of intravenous verapamil in three patients with atrioventricular block (AVB) and Torsades de Pointes (TP), to obtain indirect evidence of slow membrane channel involvement in the TP mechanism. In two cases TP were completely suppressed and in one there was marked, albeit partial, suppression. In two cases verapamil did not shorten QT, while in the third suppression verapamil was related to junctional escape acceleration and QT shortening. In one of the cases where QT was not changed, the abolition of long pauses may have played a role in TP suppression. The affect of verapamil on TP in our patients is consistent with a combination of mechanisms, including direct membrane effects (EPD inhibition) and junctional pacemaker acceleration. Verapamil might be of therapeutic value in this clinical setting.

Coronary blood flow velocity and coronary flow reserve can be assessed in humans using a coronary Doppler catheter and the vasodilator papaverine. Although it is a safe, elegant and reproducible technique, serious complications can occur. Coronary flow reserve assessment in a 49-year-old man with a critical stenosis in the proximal part of the circumflex artery was complicated by a papaverine-induced ventricular arrhythmia. Several features of the present case report support papaverine-induced disturbances of the repolarization phase as the pathophysiological mechanism: a 'torsade de pointes' pattern of the tachycardia, the lengthening of the QT-interval, the appearance of a new U-wave and the presence of additional risk factors (hypokalaemia and alcalosis). Patients presenting additional risk factors for this complication should be excluded from coronary flow reserve assessment.

Aims Treatment of atrial fibrillation remains a major clinical challenge owing to the limited efficacy and safety of anti-arrhythmic drugs, particularly in patients with structural heart disease. Methods and results To evaluate the efficacy of azimilide, a new class III anti-arrhythmic drug, we studied 658 patients with symptomatic persistent atrial fibrillation, adequate anticoagulant therapy, and planned electrical cardioversion. Patients were randomized to placebo, azimilide (125 mg o.d.), or sotalol (160 mg b.i.d.). Primary efficacy analysis was based on event recurrence, which was defined as atrial fibrillation lasting>24 h, or requiring DC cardioversion. Median time to recurrence was 14 days for azimilide, 12 days for placebo, and 28 days for sotalol ( P = 0.0320 when comparing azimilide with placebo; P = 0.0002 when comparing azimilide with sotalol). The placebo-to-azimilide hazard ratio was 1.291 (95% CI: 1.022–1.629) and the sotalol-to-azimilide hazard ratio was 0.652 (95% CI: 0.523–0.814). Adverse events causing patient withdrawal were more frequent ( P

To examine the initiating mode of Torsade de Pointes (TdP) in patients with congenital long QT syndrome (LQTS).We evaluated 111 episodes of TdP recorded on the electrocardiograms of 24 patients with congenital LQTS, and clarified the initiating mode, the three consecutive preceding RR intervals defined as C(2), C(1), and C(0), the timing of initiating premature ventricular contraction (PVC) and the cycle length (CL) of TdP. Three different initiating patterns were observed: (1) a "short-long-short" sequence (SLS) pattern (23 patients, 72 TdP, 65%) defined as one or more short-long cardiac cycles followed by an initiating short-coupled PVC (C(1)C(2) and C(0)), (2) an "increased sinus rate" (ISR) pattern (8 patients, 28 TdP, 25%) defined as a gradual increase in sinus rate with or without T-wave alternans (C(2)/=C(1)/=C(0)), and (3) a "changed depolarization" (CD) pattern (5 patients, 11 TdP, 10%) defined as a sudden long-coupled PVC or fusion beat followed by short-coupled PVC. The C(0) was shorter in ISR than SLS and CD (mean C(0): 488 vs. 587 and 603 ms, respectively; P0.05). Therefore, the initiating PVC appeared near the T-wave peak of the last beat before onset in ISR, while it occurred after the T-wave peak in SLS and CD. The CL of TdP was shorter in ISR than in SLS (256 vs. 295 ms, P0.05).Our data show the existence of three predominant initiating modes of TdP in patients with congenital LQTS and suggests a differential mechanism of initiation of TdP for each mode.

Aims The aim of this pilot study was to evaluate provocative sotalol testing to unmask abnormal repolarization due to altered myocardial electrical properties as the key feature in acquired Long-QT-Syndrome. Reliable diagnosis and risk stratification for the individual patient are complicated by the multitude of mechanisms involved in acquired QT-prolongation. The combined influence of all components determines susceptibility to arrhythmias related to QT-prolongation. Methods Twenty consecutive patients who had experienced torsades de pointes in association with QT-prolonging drugs were tested with i.v. d,l-sotalol (2mg/kg) with 24-h intensive care monitoring to evaluate the repolarization process by determining QT- and QTc-prolongations. Results were compared to age and sex matched controls. Results At baseline, no differences between control and study population with regard to QT and QTc were detected. After sotalol infusion, QTc increased from 422±17 to 450±22ms in controls and from 434±20 to 541±37ms in the study population. Torsades de pointes occurred in three out of 20 patients (15%) in the study population but in none of the control patients following i.v. sotalol testing. Conclusions Controlled exposure to sotalol successfully identifies patients with normal QTc intervals but altered myocardial repolarization. This may be useful for clarifying diagnosis and pathogenesis of acquired Long-QT-Syndrome.

The excellent PAFAC1 and SOPAT2 trials demonstrated that quinidine, in combination with verapamil, is at least equivalent to sotalol in the prevention of recurrences of atrial fibrillation (AF). The combination of verapamil with quinidine in this setting may be beneficial for several reasons. First, verapamil has the ability of suppressing after depolarizations underlying the onset of torsades de pointes, which justifies the low rate of pro-arrhythmic events observed with quinidine during the follow-up period of these trials.1–3 Secondly, it has been already demonstrated that …